Arylsulfonanilide ureas

ABSTRACT

The invention provides compounds, compositions and methods relating to novel arylsulfonanilide derivatives and their use as pharmacologically active agents. The compositions find particular use as pharmacological agents in the treatment of disease states, particularly cancer, psoriasis, vascular restenosis, infections, atherosclerosis and hypercholesterolemia, or as lead compounds for the development of such agents.

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. Ser. No. 60/100,888filed Sept. 23, 1998, the disclosure of which is incorporated herein byreference.

FIELD OF THE INVENTION

[0002] The present invention relates to arylsulfonanilide ureas andtheir use as pharmacologically active agents capable of lowering plasmacholesterol levels and inhibiting abnormal cell proliferation.

BACKGROUND OF THE INVENTION

[0003] A number of arylsulfonamides have recently been described for thetreatment of disorders and conditions arising from abnormal cellproliferation and from elevated plasma cholesterol levels. See, forexample, PCT publications WO 97/30677 and WO 98/05315.

[0004] Most prevalent among diseases stemming from abnormal cellproliferation is cancer, a generic name for a wide range of cellularmalignancies characterized by unregulated growth, lack ofdifferentiation, and the ability to invade local tissues andmetastasize. These neoplastic malignancies affect, with various degreesof prevalence, every tissue and organ in the body. A multitude oftherapeutic agents have been developed over the past few decades for thetreatment of various types of cancer. The most commonly used types ofanticancer agents include: DNA-alkylating agents (e.g.,cyclophosphamide, ifosfamide), antimetabolites (e.g., methotrexate, afolate antagonist, and 5-fluorouracil, a pyrimidine antagonist),microtubule disruptors (e.g., vincristine, vinblastine, paclitaxel), DNAintercalators (e.g., doxorubicin, daunomycin, cisplatin), and hormonetherapy (e.g., tamoxifen, flutamide). The ideal antineoplastic drugwould kill cancer cells selectively, with a wide therapeutic indexrelative to its toxicity towards non-malignant cells. It would alsoretain its efficacy against malignant cells, even after prolongedexposure to the drug. Unfortunately, none of the current chemotherapiespossess an ideal profile. Most possess very narrow therapeutic indexesand, in practically every instance, cancerous cells exposed to slightlysublethal concentrations of a chemotherapeutic agent will developresistance to such an agent, and quite often cross-resistance to severalother antineoplastic agents.

[0005] Psoriasis, a common chronic skin disease characterized by thepresence of dry scales and plaques, is generally thought to be theresult of abnormal cell proliferation. The disease results fromhyperproliferation of the epidermis and incomplete differentiation ofkeratinocytes. Psoriasis often involves the scalp, elbows, knees, back,buttocks, nails, eyebrows, and genital regions, and-may range inseverity from mild to extremely debilitating, resulting in psoriaticarthritis, pustular psoriasis, and exfoliative psoriatic dermatitis. Notherapeutic cure exists for psoriasis. Milder cases are often treatedwith topical corticosteroids, but more severe cases may be treated withantiproliferative agents, such as the antimetabolite methotrexate, theDNA synthesis inhibitor hydroxyurea, and the microtubule disruptercolchicine.

[0006] Other diseases associated with an abnormally high level ofcellular proliferation include restenosis, where vascular smooth musclecells are involved, inflammatory disease states, where endothelialcells, inflammatory cells and glomerular cells are involved, myocardialinfarction, where heart muscle cells are involved, glomerular nephritis,where kidney cells are involved, transplant rejection, where endothelialcells are involved, infectious diseases such as HIV infection andmalaria, where certain immune cells and/or other infected cells areinvolved, and the like. Infectious and parasitic agents per se (e.g.bacteria, trypanosomes, fungi, etc) are also subject to selectiveproliferative control using the subject compositions and compounds.

[0007] Psoriasis, a common chronic skin disease characterized by thepresence of dry scales and plaques, is generally thought to be theresult of abnormal cell proliferation. The disease results fromhyperproliferation of the epidermis and incomplete differentiation ofkeratinocytes. Psoriasis often involves the scalp, elbows, knees, back,buttocks, nails, eyebrows, and genital regions, and may range inseverity from mild to extremely debilitating, resulting in psoriaticarthritis, pustular psoriasis, and exfoliative psoriatic dermatitis. Notherapeutic, cure exists for psoriasis. Milder cases are often treatedwith topical corticosteroids, but more severe cases may be treated withantiproliferative agents, such as the antimetabolite methotrexate, theDNA synthesis inhibitor hydroxyurea, and the microtubule disruptercolchicine.

[0008] Other diseases associated with an abnormally high level ofcellular proliferation include restenosis, where vascular smooth musclecells are involved, inflammatory disease states, where endothelialcells, inflammatory cells and glomerular cells are involved, myocardialinfarction, where heart muscle cells are involved, glomerular nephritis,where kidney cells are involved, transplant rejection, where endothelialcells are involved, infectious diseases such as HIV infection andmalaria, where certain immune cells and/or other infected cells areinvolved, and the like. Infectious and parasitic agents per se (e.g.bacteria, trypanosomes, fungi, etc) are also subject to selectiveproliferative control using the subject compositions and compounds.

[0009] Psoriasis, a common chronic skin disease characterized by thepresence of dry scales and plaques, is generally thought to be theresult of abnormal cell proliferation. The disease results fromhyperproliferation of the epidermis and incomplete differentiation ofkeratinocytes. Psoriasis often involves the scalp, elbows, knees, back,buttocks, nails, eyebrows, and genital regions, and may range inseverity from mild to extremely debilitating, resulting in psoriaticarthritis, pustular psoriasis, and exfoliative psoriatic dermatitis. Notherapeutic cure exists for psoriasis. Milder cases are often treatedwith topical corticosteroids, but more severe cases may be treated withantiproliferative agents, such as the antimetabolite methotrexate, theDNA synthesis inhibitor hydroxyurea, and the microtubule disruptercolchicine.

[0010] Other diseases associated with an abnormally high level ofcellular proliferation include restenosis, where vascular smooth musclecells are involved, inflammatory disease states, where endothelialcells, inflammatory cells and glomerular cells are involved, myocardialinfarction, where heart muscle cells are involved, glomerular nephritis,where kidney cells are involved, transplant rejection, where endothelialcells are involved, infectious diseases such as HIV infection andmalaria, where certain immune cells and/or other infected cells areinvolved, and the like. Infectious and parasitic agents per se (e.g.bacteria, trypanosomes, fungi, etc) are also subject to selectiveproliferative control using the subject compositions and compounds.

[0011] Accordingly, it is one object of the present invention to providecompounds which directly or indirectly are toxic to actively dividingcells and are useful in the treatment of cancer, viral and bacterialinfections, vascular restenosis, inflammatory diseases, autoimmunediseases, and psoriasis.

[0012] A further object of the present invention is to providetherapeutic compositions for treating the conditions described herein.

[0013] Still further objects are to provide methods for killing activelyproliferating cells, such as cancerous, bacterial, or epithelial cells,and treating all types of cancers, infections, inflammatory, andgenerally proliferative conditions. A further object is to providemethods for treating other medical conditions characterized by thepresence of rapidly proliferating cells, such as psoriasis and otherskin disorders.

[0014] Additional objects, features and advantages will become apparentto those skilled in the art from the following description and claims.

SUMMARY OF THE INVENTION

[0015] The invention provides novel arylsulfonanilide compounds, as wellas methods and compositions relating to novel arylsulfonanilide ureasand their use as pharmacologically active agents. The compounds andcompositions find use as pharmacological agents in the treatment ofdisease states, particularly hypercholesterolemia, atherosclerosis,cancer, bacterial infections, and psoriasis, or as lead compounds forthe development of such agents. The compounds of the invention have theformula:

[0016] or a pharmaceutically acceptable salt thereof.

[0017] In the formula above, X represents an oxygen atom, a sulfur atomor NH, preferably oxygen.

[0018] The letter Y represents hydrogen, a heterocyclic ring,(C₁-C₈)alkyl, (C₁-C₈)heteroalkyl, aryl, aryl(C₁-C₄)alkyl,aryl(C₁-C₄)heteroalkyl, heteroaryl(C₁-C₄)alkyl,heteroaryl(C₁-C₄)heteroalkyl, or is optionally linked together with R³to form a 5-, 6- or 7-membered heterocyclic ring which can be aromaticor non-aromatic.

[0019] The symbols R¹, R² and R³ each independently represent hydrogen,(C₁-C₆)alkyl or (C₁-C₆)heteroalkyl. Additionally, as noted above, insome embodiments R³ is combined with Y and the adjacent nitrogen atom toform a heterocyclic ring. The symbol R⁴ represents hydrogen, halogen,(C₁-C₈)alkyl, (C₁-C8)heteroalkyl, —OR¹¹, —SR¹¹ and —NR¹¹ R¹², whereinR¹¹ and R¹² are each independently hydrogen, (C₁-C₈)alkyl or(C₁-C₈)heteroalkyl.

[0020] The symbol Ar represents a substituted aryl group selected from

[0021] in which X¹ and X² are each independently F, Cl or Br.

[0022] The methods of the present invention use pharmaceuticalcompositions containing compounds of the foregoing description of thegeneral Formula I for the treatment of pathology such as cancer,bacterial infections, psoriasis, hypercholesterolemia, atherosclerosis,pancreatitis, and hyperlipoproteinemia. Briefly, the inventions involveadministering to a patient an effective formulation of one or more ofthe subject compositions.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Not applicable

DETAILED DESCRIPTION OF THE INVENTION

[0024] Definitions

[0025] The term “alkyl,” by itself or as part of another substituent,means, unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- andmulti-radicals, having the number of carbon atoms designated (i.e.C₁-C₁₀ means one to ten carbons). Examples of saturated hydrocarbonradicals include groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl,cyclopropylmethyl, homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group isone having one or more double bonds or triple bonds. Examples ofunsaturated alkyl groups include vinyl, 2-propenyl, crotyl,2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl),ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs andisomers. The term “alkyl,” unless otherwise noted, is also meant toinclude those derivatives of alkyl defined in more detail below as“cycloalkyl” and “alkylene.” The term “alkylene” by itself or as part ofanother substituent means a divalent radical derived from an alkane, asexemplified by —CH₂CH₂CH₂CH₂—. Typically, an alkyl group will have from1 to 24 carbon atoms, with those groups having 10 or fewer carbon atomsbeing preferred in the present invention. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingeight or fewer carbon atoms.

[0026] The term “alkoxy,” employed alone or in combination with otherterms means, unless otherwise stated, an alkyl group, as defined above,connected to the remainder of the molecule via an oxygen atom, such as,for example, methoxy, ethoxy, 1-propoxy, 2-propoxy and the higherhomologs and isomers.

[0027] The term “thioalkoxy,” employed alone or in combination withother terms means, unless otherwise stated, an alkyl group, as definedabove, connected to the remainder of the molecule via a sulfur atom,such as, for example, thiomethoxy (methylthio), thioethoxy (ethylthio),1-thiopropoxy, 2-thiopropoxy and the higher homologs and isomers.

[0028] The term “heteroalkyl,” by itself or in combination with anotherterm, means, unless otherwise stated, a stable straight or branchedchain, or cyclic hydrocarbon radical, or combinations thereof, which maybe fully saturated, mono- or polyunsaturated and can include di- andmulti-radicals, consisting of the stated number of carbon atoms and fromone to three heteroatoms selected from the group consisting of O, N, Siand S, and wherein the nitrogen and sulfur atoms may optionally beoxidized and the nitrogen heteroatom may optionally be quatemized. Theheteroatom(s) O, N and S may be placed at any interior position of theheteroalkyl group. The heteroatom Si may be placed at any position ofthe heteroalkyl group, including the position at which the alkyl groupis attached to the remainder of the molecule. Examples include—CH₂—CH₂—O—CH₃, —CH₂— CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂-S—CH₂—CH₃,—CH₂—CH₂—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃ . Up to two heteroatoms may beconsecutive, such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.Also included in the term “heteroalkyl” are those radicals described inmore detail below as “heteroalkylene” and “heterocycloalkyl.” The term“heteroalkylene” by itself or as part of another substituent means adivalent radical derived from heteroalkyl, as exemplified by—CH₂—CH₂—S—CH₂CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini.Still fuirther, for alkylene and heteroalkylene linking groups, as wellas all other linking groups described herein, no specific orientation ofthe linking group is implied.

[0029] The terms “cycloalkyl” and “heterocycloalkyl”, by themselves orin combination with other terms, represent, unless otherwise stated,cyclic versions of “alkyl” and “heteroalkyl” respectively. Additionally,for heterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl,3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkylinclude 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

[0030] The terms “halo” or “halogen,” by themselves or as part ofanother substituent, mean, unless otherwise stated, a fluorine,chlorine, bromine, or iodine atom.

[0031] The term “aryl,” employed alone or in combination with otherterms (e.g., aryloxy, arylthioxy, arylalkyl) means, unless otherwisestated, an aromatic substituent which can be a single ring or multiplerings (up to three rings) which are fused together or linked covalently.The rings may each contain from zero to four heteroatoms selected fromN, O, and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quatemized. The arylgroups that contain heteroatoms may be referred to as “heteroaryl” andcan be attached to the remainder of the molecule through a carbon atomor a heteroatom. Non-limiting examples of aryl groups include phenyl,1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl,4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. Substituents for each of the above noted aryl ring systemsare selected from the group of acceptable substituents described below.

[0032] The terms “arylalkyl” and “arylheteroalkyl” are meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like) or a heteroalkylgroup (e.g., phenoxymethyl, 2-pyridyloxymethyl, 1-naphthyloxy-3-propyl,and the like). The arylalkyl and arylheteroalkyl groups will typicallycontain from 1 to 3 aryl moieties attached to the alkyl or heteroalkylportion by a covalent bond or by fusing the ring to, for example, acycloalkyl or heterocycloalkyl group. For arylheteroalkyl groups, aheteroatom can occupy the position at which the group is attached to theremainder of the molecule. For example, the term “arylheteroalkyl” ismeant to include benzyloxy, 2-phenylethoxy, phenethylamine, and thelike.

[0033] As used herein, the term “heterocycle” refers to any ring havingat least one heteroatom ring member. The term is meant to be inclusiveof both heterocycloalkyl groups, heteroaryl groups and other ringshaving one or more heteroatoms and optionally one or more unsaturatedbonds (typically, a double bond). In addition to the examples providedabove for heterocycloalkyl and heteroaryl groups, the term “heterocycle”includes 1,2,4-triazolyl, 1,3,4-thiadiazolyl, pyrazolyl,1,2,3,4-tetrazolyl and 1,2,3-triazolyl. As with heteroaryl groups,heterocyclic groups can be attached to the remainder of the moleculethrough either a carbon atom or a heteroatom ring member.

[0034] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heterocycle”) is meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

[0035] Substituents for the alkyl and heteroalkyl radicals (includingthose groups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be a variety of groups selected from: —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —CO₂R′,—CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —CN and—NO₂ in a number ranging from zero to (2N+1), where N is the totalnumber of carbon atoms in such radical. R′, R″ and R′″ eachindependently refer to hydrogen, unsubstituted(C₁-C₈)alkyl andheteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens,unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C₁-C₄)alkylgroups. When R′ and R″ are attached to the same nitrogen atom, they canbe combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.For example, —NR′R″ is meant to include 1-pyrrolidinyl and4-morpholinyl.

[0036] Similarly, substituents for the aryl groups are varied and areselected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —N₃,—CH(Ph)₂, perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a numberranging from zero to the total number of open valences on the aromaticring system; and where R′ and R″ are independently selected fromhydrogen, (C₁-C₈)alkyl and heteroalkyl, unsubstituted aryl,(unsubstituted aryl)-(C₁-C₄)alkyl, and (unsubstitutedaryl)oxy-(C₁-C₄)alkyl.

[0037] Two of the substituents on adjacent atoms of the aryl ring mayoptionally be replaced with a substituent of the formula—T—C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2. Alternatively, twoof the substituents on adjacent atoms of the aryl ring may optionally bereplaced with a substituent of the formula —A—(CH₂)_(r)—B—, wherein Aand B are independently —CH₂—, —O—, —NH—, —S—, —S(O)—, —S(O)₂—,—S(O)₂NR′— or a single bond, and r is an integer of from 1 to 3. One ofthe single bonds of the new ring so formed may optionally be replacedwith a double bond. Alternatively, two of the substituents on adjacentatoms of the aryl ring may optionally be replaced with a substituent ofthe formula —(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independentlyintegers of from 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituent R′ in —NR′— and —S(O)₂NR′— is selected fromhydrogen or unsubstituted (C₁-C₆)alkyl.

[0038] As used herein, the term “heteroatom” is meant to include oxygen(O), nitrogen (N), sulfur (S) and silicon (Si).

[0039] The term “pharmaceutically acceptable salts” is meant to includesalts of the active compounds which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the presentinvention contain relatively acidic ftunctionalities, base additionsalts can be obtained by contacting the neutral form of such compoundswith a sufficient amount of the desired base, either neat or in asuitable inert solvent. Examples of pharmaceutically acceptable baseaddition salts include sodium, potassium, calcium, ammonium, organicamino, or magnesium salt, or a similar salt. When compounds of thepresent invention contain relatively basic finctionalities, acidaddition salts can be obtained by contacting the neutral form of suchcompounds with a sufficient amount of the desired acid, either neat orin a suitable inert solvent. Examples of pharmaceutically acceptableacid addition salts include those derived from inorganic acids likehydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic,phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic,succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge, S. M., et al, “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present invention contain both basic and acidicftnctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

[0040] The neutral forms of the compounds may be regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentinvention.

[0041] In addition to salt forms, the present invention providescompounds which are in a prodrug form. Prodrugs of the compoundsdescribed herein are those compounds that readily undergo chemicalchanges under physiological conditions-to provide a compound of formulaI. Additionally, prodrugs can be converted to the compounds of thepresent invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme.

[0042] Certain compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms are equivalent to unsolvated forms and areintended to be encompassed within the scope of the present invention.Certain compounds of the present invention may exist in multiplecrystalline or amorphous forms. In general, all physical forms areequivalent for the uses contemplated by the present invention and areintended to be within the scope of the present invention.

[0043] Certain compounds of the present invention possess asymmetriccarbon atoms (optical centers) or double bonds; the racemates,diastereomers, geometric isomers and individual isomers are all intendedto be encompassed within the scope of the present invention.

[0044] The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

[0045] General

[0046] The compounds described herein are related to compounds providedin PCT publications WO 97/30677 and WO 98/05315, and to compoundsprovided in co-pending application Ser. No. 08/917,025 (filed Aug. 22,1997) and application Ser. No. 60/090,681 (Atty Docket No. T98-014,filed Jun. 25, 1998). More particularly, compounds are now described inwhich a urea or substituted urea, thiourea or substituted thiourea, orguanidine or substituted guanidine moiety is attached to anarylsulfonamidobenzene.

[0047] Embodiments of the Invention

[0048] The present invention provides novel arylsulfonanilidederivatives having the formula:

[0049] or a pharmaceutically acceptable salt thereof.

[0050] In the above formula, the letter X represents O, S, or NH,preferably O. The letter Y represents hydrogen, a heterocyclic ring,(C₁-C₈)alkyl, (C₁-C₈)heteroalkyl, aryl, aryl(C₁-C₄)alkyl,aryl(C₁-C₄)heteroalkyl, heteroaryl(C₁-C₄)alkyl orheteroaryl(C₁-C₄)heteroalkyl. Optionally, Y is linked together with R³to form a 5-, 6- or 7-membered heterocyclic ring.

[0051] In one group of preferred embodiments, Y is a substituted orunsubstituted (C₁-C₈)alkyl, or a substituted or unsubstituted(C₁-C₈)heteroalkyl. Preferably, Y is selected from 2-methoxyethyl,2-hydroxyethyl, 2,3-dihydroxypropyl and 3-hydroxypropyl.

[0052] In another group of preferred embodiments, Y is a substituted orunsubstituted heterocycle (e.g., 2-thiadiazolyl, 5-tetrazolyl,2-thiazolyl, and the like) or a substituted or unsubstituted aryl group.

[0053] In yet another group of preferred embodiments, Y is a substitutedor unsubstituted aryl(C₁-C₄)alkyl, aryl(C₁-C₄)heteroalkyl,heteroaryl(C₁-C₄)alkyl or heteroaryl(C₁-C₄)heteroalkyl group. Example ofthese groups include benzyl, phenethyl, furfurylmethyl, furfurylethyl,thienylmethyl, thienylethyl and the like. A particularly preferredmember of this group of embodiments is 2-furfurylmethyl.

[0054] In still another group of preferred embodiments, Y is combinedwith R³ and the nitrogen atom to which each is attached to form aheterocyclic ring, preferably monocyclic and having five or six ringvertices. The heterocyclic ring formed by Y, N and R³ can be substitutedor unsubstituted. Examples of such rings include 3-aminopyrazole,3-amino-1,2,4-triazole, and 4-morpholine. Particularly preferred are the3-amino-1,2,4-triazole ring and the 3-aminopyrazole ring.

[0055] Returning to the general formula above, the symbols R¹ and R² areeach independently hydrogen, (C₁-C₆)alkyl or (C₁-C₆)heteroalkyl.Preferably, R¹ and R² are each independently hydrogen or (C₁-C₄)alkyl.More preferably, R¹ and R² are both hydrogen.

[0056] The symbol R³ represents hydrogen, (C₁-C₆)alkyl or(C₁-C₆)heteroalkyl, or can be combined with Y as described above to forma heterocyclic ring. Preferably, R³ is hydrogen or is combined with Y toform a five- or six-membered heterocyclic ring.

[0057] The symbol R⁴ represents hydrogen, halogen, (C₁-C₈)alkyl,(C₁-C₈)heteroalkyl, —OR¹¹, —SR¹¹ or —NR¹¹R¹², wherein R¹¹ and R¹² areeach independently hydrogen, (C₁-C₈)alkyl or (C₁-C₈)heteroalkyl. Inpreferred embodiments, R⁴ is attached to the position para to thesulfonamide group (and ortho to the urea). Particularly preferred arethose embodiments in which R⁴ is hydrogen, (C₁-C₃)alkyl or(C₁-C₃)alkoxy, more preferably (C₁-C₃)alkoxy.

[0058] The symbol Ar represents a substituted aryl group selected from

[0059] in which X¹ and X² are each independently F, Cl or Br. In onegroup of preferred embodiments, Ar is pentafluorophenyl. In anothergroup of preferred embodiments, Ar is 2,3,4,5-tetrafluorophenyl. In yetanother group of preferred embodiments, Ar is 3,4,5-trimethoxyphenyl. Instill another group of preferred embodiments, Ar is3-methoxy-4,5-methylenedioxyphenyl.

[0060] Certain combinations of the above preferred embodiments areparticularly preferred. In a first group of preferred embodiments, thecompounds have the formula:

[0061] In this group of embodiments, R⁴ is preferably hydrogen,(C₁-C₃)alkyl, (C₁-C₃)alkoxy or (C₁-C₃)thioalkoxy, more preferably,methyl, methoxy, ethoxy or thiomethoxy. Y is preferably hydrogen, aheterocyclic ring, (C₁-C₈)alkyl, (C₁-C₈)heteroalkyl, aryl oraryl(C₁-C₄)alkyl, most preferably hydrogen.

[0062] In another group of preferred embodiments, the compounds have theformula:

[0063] In this group of embodiments, R⁴ is the same as described forformula Ia. R³ and Y are preferably combined to form a substituted orunsubstituted heterocyclic ring. Preferred groups for the ring definedby R³, Y and the nitrogen to which each is attached include3-amino-pyrazole, 3-amino-1,2,4-triazole, and 4-morpholine.

[0064] Synthesis

[0065] Compounds of the present invention can be prepared using certainintermediates and methods described in WO 97/30677 and WO 98/05315. Inone group of embodiments, arylsulfonamidoanilines can be prepared asdescribed, and the anilino amino group can then be acylated with anappropriate isocyanate derivative using conventional methods. Forexample, 2-methoxy-5-pentafluorophenylsulfonamidoaniline can be treatedwith an isocyanate (e.g., ethyl isocyanatoacetate, potassium isocyanate,and the like) to form compounds of the present invention (see, Examples5 and 6). In a similar manner, additional compounds can be formedbeginning with the appropriate aniline derivative. Using thioisocyanatesin place of isocyanates allows for the synthesis of the correspondingthioureas. A general scheme for the preparation of ureas and thioureasusing isocyanates and thioisocyanates, respectively, is provided inScheme 1, which further illustrates the preparation of guanidinederivatives from a thiourea.

[0066] As shown in Scheme 1, an arylsulfonamidoaniline i can be treatedwith an isocyanate in the presence of base to form ureas ii of thepresent invention. The bases used act as acid scavenger and aretypically tertiary amine bases such as triethylamine,diethylisopropylamine, N-methylmorpholine, pyridine and the like.Similarly, treatment of i with an appropriate isothiocyanate providestarget thioureas iii. Conversion of iii to guanidines iv can beaccomplished by treating iii with methyl iodide to form a correspondingS-methyl isothiourea, which can be treated with ammonium hydroxide toform the corresponding guanidine compound iv.

[0067] Alternatively, anilines such as2-methoxy-5-pentafluorophenylsulfonamidoaniline can be treated withtriphosgene and a suitable amine in the presence of an acid scavenger toprovide ureas of the present invention (see Examples 7 and 8). A similarreaction with thiophosgene allows the synthesis of correspondingthioureas. These approaches are illustrated in Scheme 2.

[0068] Still other methods of preparation are provided in Scheme 3. Themethods presented in this scheme are typically employed when the Argroup is incompatible with the conditions for urea, thiourea andguanidine synthesis. Accordingly, treatment of a suitable nitroanilinederivative v with either an isocyanate or an isothiocyanate provides vior viii, respectively. Reduction of the nitro group present in vi andviii can be accomplished using either hydrogenation with a palladium oncharcoal catalyst (for vi) or tin chloride and HCl (for vi or viii). Theanilines, thus produced (vii and ix) can each be sulfonylated with anappropriate aryl sulfonyl chloride (ArSO₂Cl) in the presence of an acidscavenging base. Additionally, ix can be converted to a guanidinederivative x using methyl iodide and ammonia (similar to the methoddescribed in Scheme 1). Conversion of x to the target compounds iv isaccomplished by treating the aniline x with an aryl sulfonyl chloride.

[0069] The compounds used as initial starting materials in thisinvention may be purchased from commercial sources or, alternatively,can be readily synthesized by standard procedures which are well knownto those of ordinary skill in the art.

[0070] Some of the compounds of Formula I-may exist as stereoisomers,and the invention includes all active stereoisomeric forms of thesecompounds. In the case of optically active isomers, such compounds maybe obtained from corresponding optically active precursors using theprocedures described above or by resolving racemic mixtures. Theresolution may be carried out using various techniques such aschromatography, repeated recrystallization of derived asymmetric salts,or derivatization, which techniques are well known to those of ordinaryskill in the art.

[0071] The compounds of the invention may be labeled in a variety ofways. For example, the compounds may contain radioactive isotopes suchas, for example, ³H (tritium) and ¹⁴C (carbon-14). Similarly, thecompounds may be advantageously joined, covalently or noncovalently,directly or through a linker molecule, to a wide variety of othercompounds, which may provide pro-drugs or function as carriers, labels,adjuvents, coactivators, stabilizers, etc. Such labeled and joinedcompounds are contemplated within the present invention.

[0072] Analysis of Compounds

[0073] Representative compounds and compositions were demonstrated tohave pharmacological activity in in vitro assays, e.g., they are capableof specifically modulating a cellular physiology to reduce an associatedpathology or provide or enhance a prophylaxis.

[0074] Certain preferred compounds and compositions are capable ofspecifically regulating LDL receptor gene expression. Compounds may beevaluated in vitro for their ability to increase LDL receptor expressionusing western-blot analysis, for example, as described in Tam et al. (J.Biol. Chem. 1991, 266, 16764). Established animal models to evaluatehypocholesterolemic effects of compounds are known in the art. See, forexample, Spady et al., J. Clin. Invest. 1988, 81, 300, Evans et al., J.Lipid Res. 1994, 35, 1634 and Lin et al., J. Med. Chem. 1995, 38, 277.

[0075] Certain preferred compounds and compositions display specifictoxicity to various types of cells. Certain compounds and compositionsof the present invention exert their cytotoxic effects by interactingwith cellular tubulin. For certain preferred compounds and compositionsof the present invention, that interaction is covalent and irreversible.Other compounds bind in a non-covalent manner. Compounds andcompositions may be evaluated in vitro for their ability to inhibit cellgrowth, for example, as described in Ahmed et al., J. Immunol. Methods1994, 1 70, 211. Established animal models to evaluate antiproliferativeeffects of compounds are also known in the art. For example, compoundscan be evaluated for their ability to inhibit the growth of human tumorsgrafted into immunodeficient mice using methodology similar to thatdescribed by Rygaard and Povlsen, Acta Pathol. Microbiol. Scand. 1969,77, 758, and Giovanella and Fogh, Adv. Cancer Res. 1985, 44, 69.

[0076] Formulation and Administration of Compounds and PharmaceuticalCompositions

[0077] The present invention provides methods of using the subjectcompounds and compositions to treat disease or provide medicinalprophylaxis, to slow down and/or reduce the growth of tumors, toupregulate LDL receptor gene expression in a cell, or to reduce bloodcholesterol concentration in a host, etc. These methods generallyinvolve contacting the cell with or administering to the host aneffective amount of the subject compounds or pharmaceutically acceptablecompositions.

[0078] The compositions and compounds of the invention and thepharmaceutically acceptable salts thereof can be administered in anyeffective way such as via oral, parenteral or topical routes. Generally,the compounds are administered in dosages ranging from about 2 mg up toabout 2,000 mg per day, although variations will necessarily occurdepending on the disease target, the patient, and the route ofadministration. Preferred dosages are administered orally orintravenously in the range of about 0.05 mg/kg to about 20 mg/kg, morepreferably in the range of about 0.05 mg/kg to about 2 mg/kg, mostpreferably in the range of about 0.05 mg/kg to about 0.2 mg per kg ofbody weight per day.

[0079] In one embodiment, the invention provides the subject compoundscombined with a pharmaceutically acceptable excipient such as sterilesaline or other medium, water, gelatin, an oil, etc. to formpharmaceutically acceptable compositions. The compositions and/orcompounds may be administered alone or in combination with anyconvenient carrier, diluent, etc. and such administration may beprovided in single or multiple dosages. Useful carriers include solid,semi-solid or liquid media including water and non-toxic organicsolvents.

[0080] In another embodiment, the invention provides the subjectcompounds in the form of a pro-drug, which can be metabolicallyconverted to the subject compound by the recipient host. A wide varietyof pro-drug formulations are known in the art.

[0081] The compositions may be provided in any convenient form includingtablets, capsules, lozenges, troches, hard candies, powders, sprays,creams, suppositories, etc. As such the compositions, inpharmaceutically acceptable dosage units or in bulk, may be incorporatedinto a wide variety of containers. For example, dosage units may beincluded in a variety of containers including capsules, pills, etc.

[0082] The compositions may be advantageously combined and/or used incombination with other hypocholesterolemic or antiproliferativetherapeutic or prophylactic agents, different from the subjectcompounds. In many instances, administration in conjunction with thesubject compositions enhances the efficacy of such agents. Exemplaryantiproliferative agents include cyclophosphamide, methotrexate,adriamycin, cisplatin, daunomycin, vincristine, vinblastine,vinarelbine, paclitaxel, docetaxel, tamoxifen, flutamide, hydroxyurea,and mixtures thereof. Exemplary hypocholesterolemic and/or hypolipemicagents include: bile acid sequestrants such as quaternary amines (e.g.cholestyramine and colestipol); nicotinic acid and its derivatives;HMG-CoA reductase inhibitors such as mevastatin, pravastatin, andsimvastatin; gernfibrozil and other fibric acids, such as clofibrate,fenofibrate, benzafibrate and cipofibrate; probucol; raloxifene and itsderivatives; and mixtures thereof.

[0083] The compounds and compositions also find use in a variety of invitro and in vivo assays, including diagnostic assays. For example,various allotypic LDL receptor gene expression processes may bedistinguished in sensitivity assays with the subject compounds andcompositions, or panels thereof. In certain assays and in in vivodistribution studies, it is desirable to used labeled versions of thesubject compounds and compositions, e.g. radioligand displacementassays. Accordingly, the invention provides the subject compounds andcompositions comprising a detectable label, which may be spectroscopic(e.g. fluorescent), radioactive, etc.

[0084] The following examples are offered by way of illustration and notby way of limitation.

EXAMPLES

[0085]¹H—NMR spectra were recorded on a Varian Gemini 400 MHz NMRspectrometer. Significant peaks are tabulated in the order: multiplicity(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s,broad singlet), coupling constant(s) in Hertz and number of protons.Electron Ionization (El) mass spectra were recorded on a Hewlett Packard5989A mass spectrometer. Mass spectrometry results are reported as theratio of mass over charge, followed by the relative abundance of eachion (in parentheses).

[0086] Examples 1-4 provide the synthesis of certain usefulintermediates. The remaining examples provide the preparation ofpentafluorophenylsulfonamidobenzene ureas. One of skill in the art willappreciate that similar reaction schemes can be used to prepare thecorresponding 2,3,4,5-tetrafluorophenylsulfonamidobenzene,3,4,5-trimethoxyphenylsulfonamidobenzene, and3-methoxy-4,5-methylenedioxyphenylsulfonamidobenzene derivatives.Preparation of the starting anilines for each of those series can beproduced by reduction of the corresponding nitro-containingsulfonanilide compounds, similar to the process described in Example 3.These nitro compounds are obtained by reaction of the appropriatearylsulfonyl chlorides (described in co-pending applications Ser. Nos.08/917,025 and 08/896,827) with the appropriate nitroanilines (known inthe chemical literature).

Example 1

[0087] This example illustrates the preparation of intermediate4-methoxy-3-nitroaniline.

[0088] 4-Methoxy-3-nitroaniline

[0089] To a 1M solution of 3-nitro-4-fluoroaniline (16.7 g, 107 mmol,from Aldrich Chemical Co., Milwaukee, Wis., USA) in anhydrous methanolat ambient temperature was added sodium methoxide (23.1 g, 428 mmol) andthe resulting solution was refluxed with stirring for 21 hours. Thereaction mixture was then cooled to 0° C. and a 12M solution of HCl(13.4 mL) was added dropwise followed by water (250 mL). The crudemixture was extracted three times with Et₂O (200 mL). The organic layerswere combined, washed with brine (300 mL), dried over Na₂SO₄, andconcentrated under vacuum to yield 17.5g (97%) of product as a darkbrown solid, which was used without further purification. ¹H NMR(400MHz, DMSO-d₆) δ 7.09 (d, J=9Hz, 1H), 7.01 (dd, J=2.8, 1.3Hz, 1H),6.85 (ddd, J=9, 2.8, 1.4Hz, 1H), 5.2 (s, 2H), 3.75 (s, 3H).

Example 2

[0090] This example illustrates the synthesis of intermediate2-nitro-4-pentafluoro-phenylsulfonamidoanisole.

[0091] 2—Nitro-4-pentafluorophenylsulfonamidoanisole

[0092] To a 0.4 M solution of 4-methoxy-3-nitroaniline (17.5 g, 104rimol, prepared in Example 1), in anhydrous methanol was added dropwisepentafluorophenylsulfonyl chloride (7.7 mL, 52 mmol, from AldrichChemical Co.) and the resulting mixture was stirred at ambienttemperature for 1 hour. The reaction mixture was concentrated undervacuum and purified by column chromatography (10-30% EtOAc in hexane) toyield 18.1 g (87%) of the title compound as an orange solid, mp 95-97°C. ¹H NMR (400MHz, CDCl₃) δ 7.64 (d, J=2.7Hz, 1H), 7.51 (dd, J=9, 2.7Hz,1H), 7.09 (d, J=9.0Hz, 1H), 3.95 (s, 3H). MS (El): m/z 817 (30,2M+Na-2H), 398 (30, M+), 397 (100, M−H).

Example 3

[0093] This example illustrates the preparation of intermediate2-methoxy-5-pentafluorophenylsulfonamidoaniline.

[0094] 2-methoxy-5-pentafluorophenylsulfonamidoaniline

[0095] To a 0.1 5M solution of2-nitro-4-pentafluorophenylsulfonamidoanisole (18.1 g, 45.5 rnnol,prepared in Example 2), in 100% anhydrous ethanol was added 10% Pd/C(4.84 g, 4.55 mmol). Hydrogen gas was bubbled through the solution for 1min and the resulting mixture was stirred for 24 h under 1 atmosphere ofhydrogen. The crude reaction mixture was filtered through a pad ofCelite and the filter pad was washed with ethanol (500 mL). The filtrateand wash were combined and concentrated under vacuum to yield 16.5 g(99%) of product as an off white solid which was used without furtherpurification, mp 142-143-C. ¹H NMR (400MHz, DMSO-d₆) δ 10.64 (s, 1H),6.68 (d, J=8.4 Hz, 1H), 6.44 (d, J=2.1 Hz, 1H), 6.3 (dd, J=8.4, 2.1 Hz,1H), 4.88 (bs, 2H), 3.69 (s, 3H). MS(EI): m/z 369 (100, M+H).

Example 4

[0096] This example illustrate the preparation of intermediate3-methylamino-4-methoxy-1-pentafluorophenylsulfonamidobenzene.

[0097] 3-Methylamino-4-methoxy-1-pentafluorophenylsulfonamidobenzene

[0098] To a 0.5M solution of 2-formamido-4-nitroanisole (745 mg, 3.8mmol) in dioxane was added sodium borohydride (722 mg, 19 mmol) followedby dropwise addition of glacial acetic acid (1.09 mL, 19 mmol). Thereaction mixture was refluxed for 40 minutes, then cooled to 0° C. andquenched slowly with MeOH. Excess MeOH was then added and the solutionwas concentrated under vacuum to yield 2-methylamino-4-nitroanisole. Thecrude product was dissolved in anhydrous MeOH (20 mL) and Pd/C (795 mg,0.76 mmol) was added followed by bubbling hydrogen gas through thesolution for 1 minute. The reaction mixture-was then stirred for 1.5 hunder 1 atmosphere of hydrogen. The reaction mixture was filteredthrough a pad of Celite and the filter pad was washed with MeOH (40 mL).To the combined filtrate and wash was added pentafluorophenylsulfonylchloride (282 mL, 0.26 mmol). After stirring for 30 min the reactionmixture was concentrated under vacuum and purified by columnchromatography (10-25% EtOAc in hexane) to yield 153 mg (21% for threesteps) of the title compound as a pale yellow solid. ¹H NMR (400MHz,DMSO-d₆) δ 10.7 (s, 1H), 6.68 (d, J=8.4 Hz, 1H), 6.3 (dd, J=8.3, 2.5 Hz,1H), 6.22 (d, J=2.2 Hz, 1H), 5.18 (bs, 1H), 3.7 (s, 3H), 2.6 (d, J=3 Hz,3H). MS(EI): m/z 785 (35, 2M+Na-2H), 382 (20, M+), 381 (100, M−H).

Example 5

[0099]

[0100] Potassium cyanate (36 mg, 0.45 mmol) dissolved in deionized water(0.75 mL) was added to 3 (150 mg, 0.41 mmol) dissolved in glacial aceticacid (3 mL). The cloudy reaction mixture was stirred at room temperaturefor 3 hours. The reaction mixture was poured into deionized water (50mL) and extracted 3 times with ethyl acetate (25 mL). The combinedorganic layers were washed with saturated NaHCO₃ and saturated brine.The solution was dried over MgSO₄, filtered, and concentrated underreduced pressure. The resultant white solid was recrystallized from hotethyl acetate/hexanes to give 5 (75 mg, 45%) as a white crystallinesolid. mp 226° C. ¹H NMR (CD₃CN): δ 8.73 (bs, 1H); 7.95 (d, J=2.4 Hz,1H); 7.39 (bs, 1H); 6.92-6.91 (m, 3H); 5.14 (bs, 2H); 3.83 (s, 3H).MS(ESI): m/z 410.0 (M−H).

[0101] The potassium salt of 5 was prepared by suspending 5 in deionizedwater and adding 1.0 equivalent of 1N KOH(aq). The mixture was shakenuntil solution was complete, then lyophilized to dryness. mp >250° C. ¹HNMR (D₂O): δ 7.12 (d, J=2.7 Hz, 1H); 6.96 (d, J=8.8 Hz, 1H); 6.76 (dd,J=2.7, 8.8 Hz, 1H); 3.83 (s, 3H).

Example 6

[0102]

[0103] Ethyl isocyanatoacetate (17 mL, 0.15 mmol) was added to 3 (50 mg,0.13 mmol) dissolved in chloroform (1.5 mL). The cloudy reaction mixturewas stirred at room temperature for 1 hour, at which point the reactionmixture had solidified. Acetone (2 mnL) and ethyl isocyanatoacetate (50mL, 0.45 mmol) were added and the now homogeneous reaction mixture washeated to 50° C. After 1.5 hours, solvents were removed under reducedpressure and the resultant residue directly purified by flashchromatography (silica gel, 40% to 60% ethyl acetate/hexanes). Fractionscontaining the desired product were concentrated and the residuerecrystallized from hot ethyl acetate/hexanes to give 6 (45 mg, 67%) asa white crystalline solid. mp 164-170° C. ¹H NMR (CD₃CN): δ 8.28 (bs,1H); 7.92 (d, J=2.6 Hz, 1H); 7.45 (bs, 1H); 6.92 (d, J=8.7 Hz, 1H); 6.80(dd, J=8.6, 2.6 Hz, 1H); 5.85 (bt, J=5.2 Hz, 1H); 4.15 (q, J=7.1 Hz,2H); 3.86 (d, J=5.8 Hz, 2H); 3.84 (s, 3H); 1.24 (t, J=7.1 Hz, 3H).MS(ESI): m/z 496.0 (M−H).

Example 7

[0104]

[0105] To a 25 mL round-bottom flask was added 204 mg (0.55 mmol) of 3and 2.0 mL of dry THF. The mixture was stirred until the solid dissolvedand then the flask was cooled to 0ÿC in an ice-water bath. Solidtriphosgene (54 mg, 0.18 mmol) was added to the mixture over a period oftwo minutes and the mixture was allowed to stir for an additional fiveminutes. Then 154 μL (112 mg, 1.11 mmol) of triethylamine was addeddropwise (the mixture turned a cloudy, white color). The reactionmixture was then warmed to room temperature and stirred for 15 minutes.After cooling back down to 0ÿC, a solution of 46 mg (0.55 nunol) of3-aminopyrazole in 2.0 mL of dry THF was added dropwise. The reactionmixture was once again heated to room temperature and was stirred forthree hours.

[0106] The crude mixture was poured into 5 mL of 1N HCl and wasextracted with three 20 mL volumes of ethyl acetate. The combinedorganics were washed with brine, dried over MgSO₄ and concentrated invacuo to give an off-white solid. This was purified by silica gel flashchromatography (1:3 ethyl acetate:hexanes). The resulting white solidwas recrystallized from ethyl acetate and hexanes to yield 172 mg (65%)of white crystals. mp 140-144° C. MS(ESI): m/z 476.0 (M−H). ¹H NMR(DMSO-d₆): δ 3.84 (s, 3 H); 5.36 (d, J=1.2 Hz, 1 H); 6.51 (s, 2 H); 6.90(dd, JI=6.6 Hz, J₂=1.7 Hz, 1 H); 7.05 (d, J=6.6 Hz, 1H); 7.41 (s, 1 H);7.92 (d, J=1.7 Hz); 9.53 (s, 1 H); 11.01 (s, 1 H). ES MS (M−H)⁻ theory476.0; observed 476.0. Anal. calcd. for C₁₇H₁₂F₅N₅O₄S: C42.77, H 2.53, N14.67. Found: C43.05, H 2.48, N 14.47.

Example 8

[0107]

[0108] To a 25 mL round-bottom flask was added 206 mg (0.56 mmol) of 3and 2.0 mL of dry THF. The mixture was stirred until the solid dissolvedand then the flask was cooled to 0° C. in an ice-water bath. Solidtriphosgene (55 mg, 0.19 mmol) was added to the mixture over a period oftwo minutes and the mixture was allowed to stir for an additional fiveminutes. Then 78 μL (57 mg, 1.12 mimol) of triethylamine was addeddropwise (the mixture turned a cloudy, white color). The reactionmixture was then warmed to room temperature and stirred for 15 minutes.After cooling back down to 0° C., a solution of 55 mg (0.56 mmol) of2-furfurylamine in 2.0 mL of dry THF was added dropwise. The reactionmixture was once again heated to room temperature and was stirred fortwo hours.

[0109] The crude mixture was poured into 5 mL of 1N HCl and wasextracted with three 20 mL volumes of ethyl acetate. The combinedorganics were washed with brine, dried over MgSO₄ and concentrated invacuo to give a clear oil. This oil was purified by silica gel flashchromatography (1:1 ethyl acetate:hexanes). The resulting white solidwas triturated in methanol and collected by filtration to yield 234 mg(85%) of 8 as a white powder. mp 208° C. ¹H NMR (DMSO-d₆): δ 3.77 (s, 3H); 4.23 (d, J=4.2 Hz, 2 H); 6.23 (d, J=2.3 Hz, 1 H); 6.38 (dd, J₁=2.3Hz, J₂=1.4 Hz, 1 H); 6.68 (dd, J₁=5.4 Hz, J₂=2.0 Hz, 1 H); 6.88 (d,J=6.6 Hz, 1 H); 7.24 (m, 1 H); 7.57 (t, J=0.6 Hz, 1 H); 7.87 (d, J=1.9Hz, 1 H); 8.00 (s, 1 H); 10.75 (s, 1 H). MS(ESI): 490.0 (M-H). Anal.Calcd. for C₁₉H₁₄F₅N₃O₅S: C46.44, H 2.87, N 8.55. Found: C46.64, H 2.89,N 8.52.

Example 9

[0110] This example illustrates an alternative synthesis of compound 5.

[0111] 9.1 Formylation of 2-methoxy-5-nitroaniline

[0112] Formic acid (45 mL-of 98%, 1.2 mol) was added dropwise to aceticanhydride (100 mL, 1.05 mol) at 0° C. over 15 minutes. The mixture washeated to 45-50° C. for 30 minutes, then cooled to 0° C. Anhydrous THF(100 nlL) was then added to the reaction mixture.2-Methoxy-5-nitroaniline (63 g, 375 mmol, TCl America) dissolved inanhydrous THF (200 mL) was added by addition funnel over 30 minutes. Theorange/red color of the starting material instantly disappeared uponaddition to the reaction mixture and a pale yellow solid slowlyprecipitated during the course of the addition. The addition finnel wasrinsed with 50 mL of anhydrous THF. After the addition was complete, thereaction mixture was allowed to warm to room temperature over 30minutes. The pale yellow precipitate was collected by filtration. Thefiltrate was then concentrated, triturated with ether, and the solidagain collected by filtration. After drying under high vacuum, 70.4 g(96%) of formamide 9.2 was obtained.

[0113]¹H NMR (CD₃COCD₃): δ 9.34 (bs, 1H); 8.55 (s, 1H); 8.03 (dd, J=2.8,9.1 Hz, 1H); 7.26 (d, J=9.1 Hz, 1H); 4.07 (s, 3H). MS (ESI): m/z 197.1(MH⁺), 219.1 (MNa⁺), 337 (2[MNa⁺]−H).

[0114] 9.2 Reduction of 9.2

[0115] A 500 mL 3-neck flask was charged with 10 g of formamide 9.2 and1 g of 3% Pd on carbon catalyst. The mixture was suspended in 100 mL ofMeOH, and placed under an atmosphere of hydrogen (balloon pressure).After stirring vigorously for 4 h, TLC demonstrated consumption of thestarting material. The reaction mixture was filtered and the residuewashed 3 times with 100 mL of hot acetone to ensure complete dissolutionof the product. The filtrate was concentrated, triturated with acetone,and the product collected by filtration. After drying under high vacuum,7.51 g (88%) of aniline 9.3 was obtained.

[0116]¹H NMR (CD₃COCD₃): δ 8.72 (bs, 1H); 8.39 (s, 1H); 7.78 (s, 1H);6.73 (d, J=8 Hz, 1H); 7.26 (dd, J=2, 8 Hz, 1H); 4.28 (bs, 2 H); 3.73 (s,3H). MS (ESI): m/z 167.1 (MH⁺), 189.1 (MNa⁺).

[0117] 9.3 Sulfonylation of 9.3

[0118] Aniline 9.3 (44.6 g, 268 ummol) and 2,6-lutidine (32.8 mL, 282mmol) were dissolved in 800 mL of acetone (the aniline only partlydissolved). An addition funnel was charged with C₆F₅SO₂Cl (41.8 mL, 282mrol) and the sulfonyl chloride was added over 15 minutes. During theaddition, the starting material dissolved and a new precipitate(2,6-lutidine hydrochloride) formed. After 30 minutes, the 2,6-lutidinehydrochloride was removed by filtration and the filtrate concentratedunder reduced pressure. The brown oily solid so produced was trituratedwith CH₂Cl₂ and the solid collected. A second batch of product wasobtained by repeating the concentration, trituration, and filtration.After drying under high vacuum, 95.5 g (90%) of sulfonamide 9.4 wasobtained as a pale yellow solid.

[0119]¹H NMR (CD₃COCD₃): δ 9.55 (bs, 1H); 9.01 (bs, 1H); 8.39 (s, 1H);8.17 (d, J=2.6 Hz, 1H); 7.06 (dd, J=2.6, 8.8 Hz, 1H); 6.99 (d, J=8.8 Hz,1H); 3.86 (s, 3H). MS (ESI): m/z 395.0 (M−H), 812.9 (2[M−H]+Na).

[0120] 9.4 Removal offormyl group from 9.4

[0121] Acetyl chloride (18.8 mL, 265 mmol) was carefully added toabsolute ethanol (360 mL). The mixture grew very warm (˜60° C.). Afterallowing the solution of ethanolic HCl to cool to room temperature, asuspension of sulfonamide 9.4 (95.4g, 241 mmol) in 360 mL of absoluteethanol was added. An additional 280 mL of absolute ethanol was used torinse all the starting material into the reaction mixture. All solidsdissolved within 2.5 hours. After 20 h, the reaction mixture wasconcentrated under reduced pressure to ˜100 mL total volume. The whiteprecipitate was collected by filtration, then rinsed sequentially withethanol and hexanes. The filtrate was again concentrated and theprecipitate collected and rinsed. After drying under high vacuum, 103.6g (95 %) of sulfonamide 9.5 (as the hydrochloride salt with one ethanolof salvation) was obtained as fine white crystals.

[0122]¹H NMR (CD₃OD): δ 7.40 (d, J=2.4 Hz, 1H); 7.15-7.21 (m, 2H); 4.85(bs, 5H); 3.94 (s, 3H); 3.60 (q, J=7.0 Hz, 2H); 1.18 (t, J=7.0 Hz, 3H).MS (ESI): m/z 369.0 (MH⁺).

[0123] 9.5 Conversion of 9.5 to 5

[0124] Potassium cyanate (1.72 g, 21 mmol) dissolved in deionized water(7 mL) was added to sulfonamide 9.5 (7.13 g, 19.4 mmol) dissolved inglacial acetic acid (70 mL) and water (10 mL) at 0° C. The cloudyreaction mixture was stirred for 2 hours. The reaction mixture waspoured into deionized water (300 mL) and the white precipitate wascollected by filtration. After drying under a stream of air, the productwas dissolved in hot EtOAc (400 mL) and the solution was heated toreflux. Ethyl acetate was distilled out of the flask until a very slightcloudiness was noted in the solution. The solution was allowed to coolto room temperature then placed in a refrigerator for 16 h. Whitecrystals were collected by filtration, rinsed with hexanes, and driedunder high vacuum to yield 7.33 g of 5. (NMR analysis shows that thesecrystals are ˜20% by weight ethyl acetate even after drying under highvacuum. Additional amounts of 5 can be recovered by concentrating themother liquor and repeating the crystallization process).

[0125]¹H NMR (CD₃OD): δ 7.82 (s, 1H); 6.88 (s, 2H); 7.39 (bs, 1H); 3.85(s, 3H). MS (ESI): m/z 410.0 (M−H).

[0126] 9.6 Preparation of the sodium salt of 5

[0127] Compound 5 (1.0 g, 2.41 mmol) was suspended in deionized water(10 mL). Sodium hydroxide solution (2.51 M, 1.0 mL, 2.5 nunol) was addeddropwise with vigorous stirring. Additional NaOH solution was addeddropwise until the pH of the medium was ˜10.5 and all solids haddissolved. The aqueous solution of compound 5 sodium salt was filteredto remove a very small amount of insoluble material. The solution wasthen saturated with NaCl. After 10 minutes, the precipitate of compound5, sodium salt was collected and washed with saturated brine. Thecollected solid was dried under a stream of air for 5 minutes, thenacetone was added to dissolve the sodium salt of compound 5. Thesolution was filtered (leaving behind excess NaCl) and the residue waswashed with acetone. The acetone solution was filtered a second time,then concentrated under reduced pressure. The residue was dissolved inhot acetone, and sufficient hexanes added until a very slight cloudinesswas seen. On cooling, the title compound crystallized. The precipitatewas collected, rinsed with hexanes, and dried under high vacuum to give0.73g (70 %) of compound 5, sodium salt as white crystals.

[0128]¹H NMR (D₂O): δ 7.14 (d, J=2.6 Hz, 1H); 6.93 (d, J=8.8 Hz, 1H);6.74 (dd, J=2.5, 8.7 Hz, 1H); 3.80 (s, 3H). MS (ESI): m/z 410.0 (M−H)

Example 10

[0129] Assessment of Biological Activity.

[0130] The ability of test compounds to arrest the growth of tumor cellsin culture was evaluated using HeLa cells, derived from a human cervicaladenocarcinoma, and obtained from the American Type Culture Collection(ATCC, Rockville, Md.). Cells were grown in culture in the usual way.Test compounds were dosed in triplicate at concentrations ranging from 5nM to 50 IM, and the cellular growth rate was calculated by harvestingthe cells after 72 hours of treatment and measuring their metabolicactivity using an Alamar Blue assay (Biosource International, Camarillo,Calif.). The degree of metabolic activity in the culture is proportionalto the number of living cells. See, Ahmed et al., J. Immunol. Methods1994, 170, 211. The change in growth rate for cells treated with testcompounds was normalized to the growth of untreated cells and a plot ofnormalized cellular growth vs. compound concentration was made. Theconcentration at which total growth inhibition (TGI) occurred wasdetermined. Compounds were similarly evaluated for cell growthinhibition using MCF-7/ADR cells. TABLE 1 Arylsulfonanilide Ureas

MCF-7/ Compound R HeLa TGI ADR TGI 5

+++ +++ 6

+ + 7

+++ +++ 8

+++ +++ 9

++ ++ 10

++ ++ 11

+ + 12

+ + 13

++ + 14

++ + 15

+ + 16

++ + 17

+ + 18

+++ +++ 19

+++ ++ 20

++ ++ 21

++ +

[0131] All publications and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference. Although the foregoinginvention has been described in some detail by way of illustration andexample for purposes of clarity of understanding, it will be readilyapparent to those of ordinary skill in the art in light of the teachingsof this invention that certain changes and modifications may be madethereto without departing from the spirit or scope of the appendedclaims.

What is claimed is:
 1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein X is a memberselected from the group consisting of O, S and NH; R¹ and R² are eachmembers independently selected from the group consisting of hydrogen,(C₁-C₆)alkyl and (C₁-C₆)heteroalkyl; R³ is a member selected from thegroup consisting of hydrogen, (C₁-C₆)alkyl and (C₁-C₆)heteroalkyl, or iscombined with Y and the nitrogen atom to which each is attached to forma 5-, 6- or 7-membered heterocyclic ring; R⁴ is a member selected fromthe group consisting of hydrogen, halogen, (C₁-C₈)alkyl,(C₁-C₈)heteroalkyl, —OR¹¹, —SR¹¹ and —NR¹¹ R¹², wherein R¹¹ and R¹² areeach independently selected from the group consisting of hydrogen,(C₁-C₈)alkyl and (C₁-C₈)heteroalkyl; Y is a member selected from thegroup consisting of hydrogen, a heterocyclic ring, (C₁-C₈)alkyl,(C₁-C₈)heteroalkyl, aryl, aryl(C₁-C₄)alkyl, aryl(C₁-C₄)heteroalkyl,heterocyclyl(C₁-C₄)alkyl and heterocyclyl(C₁-C₄)heteroalkyl, or isoptionally linked together with R³ to form a 5-, 6- or 7-memberedheterocyclic ring; and Ar is a member selected from the group consistingof:

wherein X¹ and X² are each independently selected from the groupconsisting of F, Cl and Br.
 2. A compound of claim 1, wherein X is O. 3.A compound of claim 1, wherein X is S.
 4. A compound of claim 1, whereinX is NH.
 5. A compound of claim 1, wherein Y is (C₁-C₆)alkyl.
 6. Acompound of claim 1, wherein Y is hydrogen.
 7. A compound of claim 1,wherein Y is a heterocyclic ring.
 8. A compound of claim 1, wherein Y iscombined with R³ and the nitrogen atom to which each is attached to forma 5- or 6-membered heterocycle.
 9. A compound of claim 1, wherein Y isselected from the group consisting of 2-thiazolyl, 1,2,4-triazolyl,1,3,4-thiadiazolyl, pyrazolyl, 1,2,3,4-tetrazolyl, imidazolyl, oxazolyland 1,2,3-triazolyl.
 10. A compound of claim 1, wherein R¹, R², R³ and Yare each hydrogen.
 11. A compound of claim 1, wherein R⁴ is selectedfrom the group consisting of hydrogen, (C₁-C₃)alkyl and (C₁-C₃)alkoxy.12. A compound of claim 1, wherein R¹, R² and R³ are each hydrogen andR⁴ is (C₁-C₃)alkoxy.
 13. A compound of claim 1, wherein R¹ and R² areeach hydrogen and Y is combined with R³ and the nitrogen atom to whicheach is attached to form a 5- or 6-membered heterocycle.
 14. A compoundof claim 1, wherein Ar is pentafluorophenyl.
 15. A compound of claim 1,wherein Ar is 2,3,4,5-tetrafluorophenyl.
 16. A compound of claim 1,wherein Ar is 3,4,5-trimethoxyphenyl.
 17. A compound of claim 1, whereinAr is 3-methoxy-4,5-methylenedioxyphenyl.
 18. A compound of claim 1,wherein R¹, R² and R³ are hydrogen, R⁴ is located in the para-positionrelative to the sulfonamide moiety and is selected from the groupconsisting of hydrogen, (C₁-C₃)alkyl, (C₁-C₃)alkoxy and(C₁-C₃)thioalkoxy, and Y is hydrogen or (C₁-C₃)alkyl.
 19. A compound ofclaim 1, wherein Ar is pentafluorophenyl; R¹, R² and R³ are eachhydrogen; R⁴ is 4-methoxy; and Y is hydrogen or (C₁-C₃)alkyl.
 20. Acompound of claim 1, represented by the formula:


21. A compound of claim 1, represented by the formula:


22. A compound of claim 1, represented by the formula:


23. A compound of claim 1, represented by the formula:


24. A compound of claim 1, represented by the formula:


25. A method of treating or preventing a disease state characterized byabnormally high levels of low density lipoprotein particles orcholesterol in the blood, or by an abnormally high level of cellproliferation, which method comprises administering to a mammaliansubject in need thereof a therapeutically effective amount of acomposition comprising a compound of formula:

or a pharmaceutically acceptable salt thereof, wherein X is a memberselected from the group consisting of O, S and NH; R¹ and R² are eachmembers independently selected from the group consisting of hydrogen,(C₁-C₆)alkyl and (C₁-C₆)heteroalkyl; R³ is a member selected from thegroup consisting of hydrogen, (C₁-C₆)alkyl and (C₁-C₆)heteroalkyl, or iscombined with Y and the nitrogen atom to which each is attached to forma 5-, 6- or 7-membered heterocyclic ring; R⁴ is a member selected fromthe group consisting of hydrogen, halogen, (C₁-C₈)alkyl,(C₁-C₈)heteroalkyl, —OR¹¹, —SR¹¹ and —NR¹¹R¹², wherein R¹¹ and R¹² areeach independently selected from the group consisting of hydrogen,(C₁-C₈)alkyl and (C₁-C₈)heteroalkyl; Y is a member selected from thegroup consisting of hydrogen, a heterocyclic ring, (C₁-C₈)alkyl,(C₁-C₈)heteroalkyl, aryl, aryl(C₁-C₄)alkyl, aryl(C₁-C₄)heteroalkyl,heterocyclyl(C₁-C₄)alkyl and heterocyclyl(C₁-C₄)heteroalkyl, or isoptionally linked together with R³ to form a 5-, 6- or 7-memberedheterocyclic ring; and Ar is a member selected from the group consistingof:

wherein X¹ and X² are each independently selected from the groupconsisting of F, Cl and Br.
 26. A method in accordance with claim 25,wherein the disease state is cancer or a cancerous condition.
 27. Amethod in accordance with claim 25, wherein the proliferative diseasestate is infection by a microorganism.
 28. A method in accordance withclaim 25, wherein the proliferative disease state is psoriasis.
 29. Amethod in accordance with claim 25, wherein the proliferative diseasestate is vascular restenosis.
 30. A method in accordance with claim 25,wherein the disease state is hypercholesterolemia or another diseasestate associated with abnormally high levels of cholesterol orlipoproteins.
 31. A method in accordance with claim 25, wherein thecompound is administered orally.
 32. A method in accordance with claim25, wherein the compound is administered intravenously, intramuscularly,subcutaneously or intraduodenally.
 33. A pharmaceutical compositioncomprising a pharmaceutically acceptable excipient and a compound havingthe formula:

or a pharmaceutically acceptable salt thereof, wherein X is a memberselected from the group consisting of O, S and NH; R¹ and R² are eachmembers independently selected from the group consisting of hydrogen,(C₁-C₆)alkyl and (C₁-C₆)heteroalkyl; R³ is a member selected from thegroup consisting of hydrogen, (C₁-C₆)alkyl and (C₁-C₆)heteroalkyl, or iscombined with Y and the nitrogen atom to which each is attached to forma 5-, 6- or 7-membered heterocyclic ring; R⁴ is a member selected fromthe group consisting of hydrogen, halogen, (C₁-C₈)alkyl,(C₁-C₈)heteroalkyl, —OR¹¹, —SR¹¹ and —NR¹¹R¹², wherein R¹¹ and R¹² areeach independently selected from the group consisting of hydrogen,(C₁-C₈)alkyl and (C₁-C₈)heteroalkyl; Y is a member selected from thegroup consisting of hydrogen, a heterocyclic ring, (C₁-C₈)alkyl,(C₁-C₈)heteroalkyl, aryl, aryl(C₁-C₄)alkyl, aryl(C₁-C₄)heteroalkyl,heterocyclyl(C₁-C₄)alkyl and heterocyclyl(C₁-C₄)heteroalkyl, or isoptionally linked together with R³ to form a 5-, 6- or 7-memberedheterocyclic ring; and Ar is a member selected from the group consistingof:

wherein X¹ and X² are each independently selected from the groupconsisting of F, Cl and Br.
 34. A composition of claim 33, wherein Ar isselected from the group consisting of


35. A composition of claim 33, wherein Ar is pentafluorophenyl.
 36. Acomposition of claim 33, wherein Ar is 2,3,4,5-tetrafluorophenyl.
 37. Acomposition of claim 33, wherein Ar is 3,4,5-trimethoxylphenyl.
 38. Acomposition of claim 33, wherein Ar is3-methoxy-4,5-methylenedioxyphenyl.
 39. A composition of claim 33,further comprising an antiproliferative agent selected from the groupconsisting of cyclophosphamide, methotrexate, adriamycin, cisplatin,daunomycin, vincristine, vinblastine, vinarelbine, paclitaxel,docetaxel, tamoxifen, flutamide, hydroxyurea, and mixtures thereof. 40.A composition of claim 33, further comprising a member selected from thegroup consisting of hypocholesterolemic and hypolipemic agents.